Myocardial ischemia, infarction, and heart failure constitute a disease spectrum which is rapidly becoming one of the foremost global health challenges. Current therapies focus upon pharmacologic optimization and macrorevascularization via PCI and CABG. Reconstructive and replacement therapies are limited in applicability or availability. A significant unmet need is that of microrevascularizatio. Repeated studies have demonstrated survival advantage in patients with robust collateralization. Thus the presence of endogenous revascularization and repair mechanisms exist and the benefits are clear; but the native potency is generally inadequate. In the initial funding period, we studied the primary effectors of endogenous microrevascularization, endothelial progenitor stem cells (EPC) and their potent chemokine stromal cell derived factor 1-alpha(SDF). We were able to significantly augment microvascular angiogenesis and improve local tissue biomechanical properties, ventricular geometry and cardiac function after myocardial ischemic injury. Via computational protein engineering, we then designed and synthesized a supra-efficient SDF analog as well as constructed a tissue engineered EPC extracellular-matrix simulating scaffold as an EPC delivery system that enhanced cell retention and survival. Elements of our work have been upscaled into a preclinical sheep model and also translated into a recently initiated human clinical trial at our institution. In this revised renewl application we propose to study in further depth the specific interactive mechanisms underlying SDF-mediated EPC neovasculogenesis, develop novel, cytokine and cell delivery platforms, and advance a potential therapeutic sustained release cytokine strategy in our preclinical sheep model. Specific Aim 1 will focus on elucidating mechanistic insights via a novel cardiac-specific SDF conditional knockout mouse, eGFP marrow reconstitution and EPC tracking, and optical fluorescence quantification of cellular level perfusion and biomechanical alterations. Specific Aim 2 will develop an innovative sustained release cytokine hydrogel composite and a unique smooth muscle cell-EPC bilevel cell sheet to deliver biologically supported EPCs to the heart. Specific Aim 3 will transition the hydrogel cytokine therapeutic strategy into a preclinical sheep model in a minimally invasive operative approach. We have generated the preliminary scientific components and assembled the team expertise to hopefully successfully achieve these goals.